1. Field of the Invention
The present invention relates to methods of treating mammals in need of such treatment with an analgesics composition containing 1-benzyl-1-hydroxy-2,3-diamino-propyl amines, 3-benzyl-3-hydroxy-2-amino-propionic acid amides or related compounds.
2. Background Art
1-Phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) was discovered by Vunam, R. R. and Radin, N., Chem. Phys. Lipids, 26, 265-278, 1980. Preparation of PDMP is described in Inokuchi, J. et al., J. Lipid Res. 28, 565-571, 1987; Radin, A. et al., NeuroProtocols, 3(2), 145-55, 1993; Radin, A. et al., J. Lipid Res. 36, 611-621, 1995 and U.S. Pat. No. 5,916,911.
These derivatives inhibit glucosylceramide (GlcCer) formation by inhibiting the enzyme GlcCer synthase, thereby lowering the level of glycosphingolipids.) The isomers most active have the R,R-(D-threo)-configuration. Four enantiomers are produced during the synthesis. Because only the D-threo enantiomers are active in inhibiting the glucosylceramide synthase, resolution of the active D-threo inhibitors was performed by chiral chromatography.
Moreover, D-threo-PDMP has antitumor activity via inhibition of glycosphingolipid biosynthesis as described by Inokuchi J., Cancer Letters 38(1-2), 23-30, 1987.

Furthermore, it was also reported that D-threo-PDMP suppresses synaptic function by Mizutani A. et al., Biochem. Biophys. Res. Commun., 222, 494-498, 1996.
Preparation of enantiomerically pure D-threo-PDMP has been reported by Mitchell, Scott A. [J. Org. Chem., 63 (24), 8837-8842, 1998]; Miura, T. et al, [Bioorg. Med. Chem., 6, 1481-1498, 1998]; Shin, S. et al., [Tetrahedron asymmetry, 11, 3293-3301, 2000]; WO 2002012185
L-threo-PDMP is an agent for treating neuronal diseases WO 95/05177. This compound is also described to be an agent for protecting brain in U.S. Pat. No. 6,407,064. Moreover treatment with L-threo-PDMP after transient forebrain ischemia in rats ameliorated the deficit of a well learned spatial memory by an 8-arm maze task, suggesting a potential for neurodegenerative disorders as described by Inokuchi et al., Ann. N.Y. Acad. Sci., 845(1), 219-224, 1998 and JP 10324671 (Seikagaku Kogyo Co.).
A stereoselective synthesis of enantiomerically pure D-threo-PDMP has also been described by Shin, S. et al., Tetrahedron asymmetry, 11, 3293-3301, 2000 and WO 2002012185 the key step is the regioselective cleavage by nitrogen nucleophiles, as morpholine, of the C(3)-N-bond of non-activated enantiomerically pure aziridine-2-methanols.

On the other hand, the synthesis of enantiomerically pure (1S,2S)-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (L-threo-PDMP) from L-serine has also been described by Mitchell, Scott A., J. Org. Chem., 63 (24), 8837-8842, 1998.

Other known methods to obtain L-threo-PDMP are described by Miura, T. et al, Bioorg. Med. Chem., 6, 1481-1498, 1998 and in JP-A-9-216858.
L-threo-PDMP is an agent for treating neuronal diseases WO 95/05177. This compound is also described to be an agent for protecting brain in U.S. Pat. No. 6,407,064. Moreover treatment with L-threo-PDMP after transient forebrain ischemia in rats ameliorated the deficit of a well learned spatial memory by an 8-arm maze task, suggesting a potential for neurodegenerative disorders as described by Inokuchi et al., Ann. N.Y. Acad. Sci., 845(1), 219-224, 1998 and JP 10324671 (Seikagaku Kogyo Co.).
Synthesis of (1S,2S)-threo- and (1R,2S)-erythro-1-phenyl-2-palmitoylamino-3-N-morpholino-1-propanol (PPMP) were described starting from Garner aldehyde of L-serine, by Nishida, A., Synlett, 4, 389-390, 1998.

Compounds with longer chain fatty acyl groups (than decanoyl) have been found to be substancially more effective as inhibitor of GCS. D-threo-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (P4 or PPPP) analogues were first obtained by a Mannich reaction as described Abe, A. et al., J. Biochem., 111, 191-196, 1992 or U.S. Pat. No. 5,916,911 and WO 2001004108.

Preparation of D-threo-4′-hydroxy-P4, one of the most potent inhibitor of GCS, was described by Lee, L. et al., J. Biol. Chem., 274, 21, 14662-14669, 1999. In addition, a series of dioxane substitutions was designed and tested. These included 3′,4′-methylenedioxyphenyl-3′,4′-ethylenedioxyphenyl-, and 3′,4′-trimethylenedioxyphenyl-substituted homologues.

Synthesis of enantiomerically pure D-threo-1-phenyl-2-benzyloxycarbonylamino-3-pyrrolidino-1-propanol (PBPP) and D-threo-P4 and its analogues from N-benzyloxycarbonyl-D-serine, was described by Jimbo M. et al, J. Biochem., 127(3), 485-91, 2000 and EP 782992 (Seikagaku Kogyo Co.). PBPP is described as a potent GCS inhibitor.

Novel prodrugs of P4 derivatives were described in US 20020198240 and WO 2002062777.
Synthesis of enantiomerically pure of D-threo-ethylenedioxy-P4 and D-threo-p-methoxy-P4 were described by Husain A. and Ganem B., Tetrahedron Lett., 43, 8621-8623, 2002. The key step is a highly syn-selective additions of aryl Grignard reagents to Garner aldehyde.

Diastereoselective synthesis of P4 analogues were described in US03/0153768 and WO 2003045928 (Genzyme Corp.); Oxazolines I [R1=(un)substituted aryl; R2, R3═H, (un)substituted aliphatic; NR2R3=heterocyclic] are prepared as intermediates for P4 glucosyltransferase inhibitors from R1CHO and R2R3NCOCH2CN. Thus, methyl isocyanoacetate CNCH2CO2Me was treated with pyrrolidine and the amide was treated with 1,4-benzodioxane-6-carboxaldehyde, followed by hydrolysis of the oxazoline using HCl in methanol, reduction of the keto group of amide II using LiAlH4, and acylation with palmitoyl chloride to give D,L-threo-ethylenedioxy-P4 III.

Synthesis of enantiopure P4 analogues were described in WO 2003008399 (Genzyme Corp.). P4 derivatives, such as I [R1, R5=un(substituted) aromatic; R2, R3═H, un(substituted) aliphatic; NR2R3=(un)substituted non-aromatic heterocyclic ring; R4=0, H2], were prepared for their therapeutic use as GCS inhibitors. Thus, D-threo-ethylenedioxy-P4 was prepared via a multistep synthetic sequence starting from S-(+)-Ph glycinol, phenyl-α-bromoacetate, 1,4-benzodioxan-6-carboxaldehyde, pyrrolidine and palmitoyl chloride.

New D-threo-P4 analogues that bear ether substituents on the aromatic ring have been recently synthesized from D-serine and found to suppress neurite extension in an embryonic insect cell line as described by Slavish., J. P. et al., Bioorg. Med. Chem. Lett., 14, 1487-1490, 2004.
Further references which serve as background to the present invention are U.S. Pat. Nos. 5,945,442; 5,952,370; 6,030,995 and 6,051,598; Journal of Labelled Compounds & Radiopharmaceuticals (1996), 38(3), 285-97; Published PCT application WO 01/38228; and Kastron et al. Latvijas PSR Zinatnu Akademijas Vestis, Kimijas Serija (1965) (4), 474-7.